We previously found that overexpression of Stat5 proteins can increase peripheral CD8+
T cell numbers by augmenting proliferation and cell survival (15
), but we did not anticipate that such overexpression would predispose to malignant transformation. The dysregulated expression of the transgenic Stat5 proteins could theoretically result in a state of hyperresponsiveness to cytokines, and in fact the level of Stat5 DNA binding activity in response to IL-2 or IL-7 was higher than seen in WT mice. However, Stat5 was not constitutively activated, and our DNA microarray gene expression studies revealed relatively few differences in gene expression between T cells from WT mice and mice overexpressing Stat5b but lacking lymphoma. Nevertheless, it is possible that transient cytokine-mediated activation at critical time points plays an important role in tumorigenesis in these animals. Interestingly, there was an increased rate/incidence of lymphomas in Stat5b transgenic mice expressing a TCR transgene, or after immunization. This is potentially consistent with antigen/adjuvant-mediated cytokine production (38
), which in turn could, at least transiently, activate the transgenic Stat5. However, sustained Stat5 activation was not observed. Nevertheless, as shown in E in Stat5b/5C.C7 double transgenic mice, a number of genes were induced over time. Additional work is needed to clarify the potential role of these genes in oncogenesis. In addition to the Stat5 transgene acting in a classical tyrosine phosphorylation-dependent manner, alternative mechanisms are possible. For example, Stat1 has been shown to affect expression of certain genes by a mechanism independent of its tyrosine phosphorylation (39
). Such a mechanism could potentially apply to other STAT proteins as well.
Given that Stat5 can be activated in D10 cells (a T helper cell clone) after TCR signaling (40
), and that T cells from Stat5a−/−
double knockout mice fail to proliferate in response to anti-CD3 stimulation (25
) and have defective ERK activation (our unpublished observations), we hypothesize that Stat5 transgenic mice might be more susceptible to the effects of TCR-stimulation in vivo. As CD8+
T cell expansion and CD8+
lymphomas are seen even in mice expressing the class II–restricted 5C.C7 TCR transgene, this indicates a particularly potent effect of the Stat5 transgene in controlling CD8+
T lineage development. Moreover, the fact that the tumors arise earlier in mice expressing a transgenic TCR or after immunization indicates a role for TCR signaling and possibly selection in the earlier development of these tumors.
In contrast to systems that have correlated constitutively activated STAT proteins with oncogenesis, our Stat5a and Stat5b transgenic models demonstrate that overexpression of a WT (HA-tagged) STAT protein can also predispose to malignant transformation. Because the transgenic vector we used directs high level expression in lymphoid tissue, it is not surprising that the tumors that developed in our mice were lymphomas. However, given the ubiquitous expression of Stat5 proteins and the fact that they are activated by many different cytokines and growth factors, we hypothesize that the oncogenic potential of Stat5a and Stat5b may not be restricted to the immune system, and that overexpression in other tissues might cause other forms of neoplasia. Accordingly, Stat5a and Stat5b could prove to be rational target molecules for manipulating the growth of a number of different tumors. Finally, the fact that TCR/antigen stimulation could augment the rate of lymphoma formation in Stat5 transgenic mice has implications related to tumor and vaccine immunology.